ORIGINAL ARTICLE Meta-Analyses of Placebo-Controlled Trials of Acamprosate for the Treatment of Alcohol Dependence Impact of the Combined Pharmacotherapies and Behavior Interventions Study George Dranitsaris, MPharm, Peter Selby, MD, and Juan Carlos Negrete, MD Objectives: The Combined Pharmacotherapies and Behavior Inter- ventions Study (COMBINE) reported no significant difference be- tween acamprosate and placebo in the treatment of alcohol depen- dence. To evaluate the impact of COMBINE, we performed a meta-analysis of acamprosate placebo-controlled trials with the inclusion of data from COMBINE. As a secondary analysis, we added the COMBINE data to a recently published meta-analysis of naltrexone placebo-controlled trials. Methods: A structured literature search of major databases was performed from January 1990 to August 2007 for acamprosate placebo-controlled randomized trials. Mean differences in cumula- tive abstinent days (CAD) and abstinence rates (AR) from eligible studies were statistically combined to calculate point estimates and 95% CI for differences in CAD and AR. Results: Ten and 16 studies evaluating CAD and AR, respectively were suitable for statistical pooling. The findings revealed that acamprosate was superior to placebo in the mean number of CAD (P  0.001) and AR (pooled AR  1.58; P  0.001). The pooled AR for naltrexone was also significant indicating a relative benefit over placebo (AR  1.27; P  0.001). The COMBINE trial results contributed a weight of less than 15% to the final pooled statistical outcomes for both agents. Conclusions: The current study confirmed that acamprosate and naltrexone are both effective agents for the treatment of patients with alcohol dependence. Systematic reviews with meta-analyses of randomized controlled trials and randomized controlled trials with adequate sample sizes are in the same (highest) level of evidence. Therefore, clinicians should use both these sources of information as their foundation for selecting optimal therapy for patients with alcohol dependence. Key Words: alcohol dependence, acamprosate, naltrexone, meta-analysis (J Addict Med 2009;: 000 –000) A lcohol dependence is a global problem. In the United States alone, it has been estimated that over 700,000 people receive treatment for this condition. 1 Alcohol abuse and dependence in the United States accounts for the loss of 100,000 lives per year, and alcohol is implicated in 30% of all traffic fatalities. 2 The misuse of alcohol also has a substantial impact on the economy. In one study from the United States, the economic cost of alcohol abuse and dependence was estimated to be more than $184 billion in 1992 dollars. 3 In Canada, alcohol abuse accounts for approximately $7.52 billion in costs, including $4.14 billion for lost productivity, $1.36 billion for law enforcement, and $1.30 billion in direct health care costs. 4 Therefore, any intervention that effectively reduces the incidence of alcohol dependence will have a major impact on societal costs. Psychological counseling and 12-step inspired treat- ment programs have been the mainstay of alcohol depen- dence clinical management, whereas pharmacologic agents have mostly played an adjunctive role. 5,6 However, there is a growing body of evidence supporting a more central role for medications in the treatment of alcohol dependence. 6,7 To date, 3 medications— disulfiram, naltrexone, and acampro- sate have approved indications for the treatment of alcohol dependence in the United States and Europe. 7 Disulfiram carries the risk of toxicity and is contraindicated in many patients. Naltrexone is an opioid antagonist and therefore cannot be used in patients who require opiate therapy; and may also be contraindicated in some patients with significant liver damage. Acamprosate does not undergo metabolism in the liver and is eliminated unchanged through the kidneys. Therefore, it is contraindicated in cases of severe renal insufficiency. 8,9 However, in patients with moderate renal impairment (creatinine clearance of 30 –50 mL/min), a re- duced dose may be safely administered. 8 From the Addictions Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada; and Addictions Unit, McGill University Health Centre, Montreal, Canada. Received for publication December 28, 2007; accepted May 27, 2008. Send correspondence and reprint requests to George Dranitsaris, Statistical Consultant, 283 Danforth Avenue, Suite 448, Toronto, Canada M4K 1N2. E-mail: gdranit@ca.inter.net Supported by Prempharm Inc., the Canadian distributor of acamprosate. The corresponding author had full access to the data in the study, conducted the analysis and had the final responsibility for the decision to submit the article. George Dranitsaris received support from Prempharm Inc. to perform the analysis. All of the co-authors participated in a medical advisory board meeting hosted by the sponsor. Copyright © 2009 American Society of Addiction Medicine ISSN: 1921– 0629/09/0000-0001 J Addict Med • Volume , Number , 2009 1